The factors involved in the regulation of the switch from fetal to adult hemoglobin in Man are not understood. This problem has important bearings on the possible therapy of sickle cell anemia and thalassemia. The problem is being approached in three ways: (1) the genetic and acquired disorders associated with persistent or reactivated fetal hemoglobin production in adult life are being further defined; (2) the in vitro red cell colony forming system is being characterized as a potential model for studying hemoglobin switching, and (3) the sheep model is being explored both in terms of the possible endocrine regulation of hemoglobin switching and also for studies on the environmental regulation of hemoglobin production using bone marrow transplantation from fetal to adult and adult to fetal sheep.